Gpcr Family Overview

A wide variety of extracellular stimuli including photons, ions, neurotransmitters, peptides, and lipids can elicit intracellular signaling events through activation of cell surface GPCRs. These receptors all share a common heptahelical transmembrane-spanning structure that allows the interaction of external stimuli at selective binding sites in extracellular domains or within the transmembrane-spanning domains of GPCRs. This binding in turn conveys conformational changes in the GPCRs, promulgating a cascade of signaling events initiated by the activation of coupled hetero-trimeric G proteins from which GPCRs derive their name. GPCRs couple to a variety of heterotrimeric G proteins including those from the Gas, Gai/o, Gaq, and Ga12/13 families that in turn activate adenylate cyclase, inhibit adenylate cyclase, activate phospholipase C-p, and activate phospholipase C-p small molecular weight G proteins, respectively. A detailed description of GPCR signal transduction can be found in Chapter 2.

Family Current Status Endogenous Ligand Subfamily Drugs

Family A

(Rhodopsin-like)

Non-liganded

Amines

Prostanoid

Nucleotide

Lipid

110 targets)

-Adrenergic -Adrenergic Dopamine Histamine Muscarinic Serotonin

Angiotensin Opioid

Somatostatin

Prostaglandin P2Y Purinergic Leokotriene Orphans

Tamsulosin, Terazosin

Albuterol, Salmeterol, Atenolol, Metoprolol

Risperidone, Haloperidol

Cetirizine, Fexofenadine, Ranitidine

Ipratropium, Tolterodine

Quetiapine, Sumatriptan

Cardesartan, Losartan, Valsartan

Codeine, Hydrocodone, Morphine, Oxycodone,

Octreotide

Latanoprost Clopidrogel Montelukast

40 targets) Liganded

Non-liganded

110 targets)

Liganded

Family B

(25 targets)

(Secretin-like)

Non-liganded

Calcitonin Calcitonin (MiacalcinĀ®)

Gonadotropin-

releasing hormone Leuprolide, Goserelin

Glucagon

Secretin

Calcitonin Calcitonin (MiacalcinĀ®)

Gonadotropin-

releasing hormone Leuprolide, Goserelin

Glucagon

Secretin

40 targets) Liganded

Family C

(11 targets)

(Metabotropic Glutamate-like)

Non-liganded

5 targets)

Family F/S

GABAb

Metabotropic

Glutamate

Orphans

Frizzled/Smoothened

FIGURE 3.1 GPCR family tree showing representative drugs targeting receptors. (Adapted from Chalmers, D.T. and Behan, D.P. Nat. Rev. Drug Disc. 2002; 1:599-608. With permission.)

GPCRs can be classified into four families based upon sequence similarity (Figure 3.1).2-5 Family A is the largest of the three represented by the rhodopsin receptor, with many of its members sharing similar sequence motifs such as the third transmembrane DRY and seventh transmembrane NPXXY domains. Family A consists of approximately 180 liganded GPCRs, 110 orphan GPCRs (Figure 3.1), and approximately 350 olfactory GPCRs,45 thus including nearly 70% of non-olfactory GPCRs and nearly 90% of total GPCRs. Family A is represented by the biogenic amine (adrenergic, muscarinic, dopaminergic, histaminergic, etc.), peptide (opioid, angiotensin II, etc.), nucleotide, and prostanoid receptors, among others (see Figure 3.1).

Family B is classified according to structural similarity to the secretin receptor. The structural hallmark of this family is a large extracellular N-terminal domain that contains consensus sites for protein-protein interactions. This family is composed of approximately 25 liganded and 40 orphan GPCRs (Figure 3.1). Calcitonin- and gonadotropin-releasing hormone receptors are representative members of this family

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